Specific Aims. Chemical reaction development has historically been guided by problems in organic synthesis or interest in developing chemical transformations of broad scope and utility. Chemical methodology development, on the other hand, has increasingly relied on systematic evaluation of variables (e.g. solvent, temperature, and ligands). We recently formulated a new approach to chemical reaction discovery that we have termed "multidimensional reaction screening".1 In this approach, chemical reactions are evaluated using multiple variables in array format. Screens typically include hundreds of reactions which are subsequently analyzed (NMR and LC/MS) followed by structure elucidation to identify new chemotypes and reaction processes. In other CMLD-BU projects, we have taken a "reaction discovery"2 approach in which substrates or scaffolds are profiled for their chemical reactivity and used to access novel chemotypes. In this project, we will outline a series of sub-projects in the general area of reaction screening and discovery. Specific libraries to be synthesized using methodologies developed are also described. 1. Development and Applications of Enantioselective Aza-Ene Reactions of NDiphenylphosphinylimines. We will screen a number of chiral ligands and reaction conditions in aza-ene reactions of phosphinylimines with exocyclic alkenes to afford chiral, non-racemic, homoallylic trifluoroacetamides. Further transformations to spiroindane libraries and polycyclic sp/ro-oxindoles will be described. 2. Reaction Discovery Employing Scaffolds Derived from Metal Carbenoid Reactions of Polyketide-like Building Blocks. We will prepare a series of scaffolds by various rhodium (ll)-catalyzed carbenoid reactions with vinyl diazo esters derived from enantioselective crotylations developed at the CMLD-BU. Scaffolds will be subjected to both Heck and radical cyclization reactions to access complex structures. 3. Complex Chemotypes Derived from Reaction Screening of Hydroxyalkyl Azides and Carbonyl Compounds. In a collaborative effort with Jeff Aube and coworkers at the KU-CMLD, we will investigate a number of structurally interesting carbonyl substrates in reactions with hydroxyalkyl azides. A second aim will be to apply reaction screening approaches to select iminium ether scaffolds identified in the first study. Based on both screening efforts, libraries of complex lactams and related structures are planned which should be very useful for biological screening efforts. 4. Reaction Screening and Scaffold Diversity via Tandem Dienone-Photorearrangement-Cycloaddition. We will utilize products of the intra- and intermolecular tandem dienone-photorearrangement-cycloaddition reactions (DPCR) as scaffolds for generation of complex structures. An asymmetric DPCR process will be investigated and products utilized to prepare complex libraries. 5. Reaction Discovery and Screening: Natural Products as Scaffolds for Structural Elaboration. In this project, we will employ natural products including the anthelmintic macrolide ivermectin and the antiangiogenesis natural product fumagillol as scaffolds for reaction screening and library synthesis.